Compounds having muscarinic receptor antagonist and beta2 adrenergic receptor agonist activity

Abstract

Compounds of formula (I) act both as muscarinic receptor antagonists and beta2 adrenergic receptor agonists and are useful for treating and/or preventing broncho-obstructive and inflammatory diseases.

The invention claimed is: 
     
       1. A compound of formula (I): 
       
         
           
           
               
               
           
         
       
       wherein:
 Q is a group of formula Q1, Q2, Q3, Q4, Q5, or Q6: 
 
       
         
           
           
               
               
           
         
         Z is H or OH; 
         Y is —(CH 2 ) n — wherein n is an integer of 1 to 12 or is a divalent group of formula Y1: 
       
       
         
           
           
               
               
           
         
         wherein: 
         A1 and A2 are, each independently, absent or are selected from the group consisting of (C 1 -C 6 )alkylene, (C 3 -C 8 )cycloalkylene, and (C 3 -C 8 )heterocycloalkylene; 
         B is absent or is selected from the group consisting of (C 3 -C 8 )cycloalkylene, (C 3 -C 8 )heterocycloalkylene, arylene, and heteroarylene or is a group of formula B1 
       
       
         
           
           
               
               
           
         
         C is absent or is selected from the group consisting of —O—, —OCO—, —C(O)O—, —S—, —S(O)—, —S(O) 2 —, and —N(R 4 )— or is one of the following groups C1-C10: 
       
       
         
           
           
               
               
           
         
         wherein R 4  is H or is selected from the group consisting of (C 1 -C 8 )alkyl, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )heterocycloalkyl, aryl, and heteroaryl; 
         D is selected from the group consisting of (C 1 -C 12 )alkylene, (C 2 -C 12 )alkenylene, and (C 2 -C 6 )alkynylene, optionally substituted by one or more (C 1 -C 6 )alkyl; 
         R is —H or (C 1 -C 4 )alkyl; 
         X is —O— or —S—; 
         R 1  is H or is selected from the group consisting of (C 3 -C 8 )cycloalkyl, aryl, heteroaryl, aryl(C 1 -C 6 )alkyl, heteroaryl(C 1 -C 6 )alkyl, and (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl, optionally substituted by one or more (C 1 -C 4 )alkoxy; 
         R 2  is selected from the group consisting of (C 3 -C 8 )cycloalkyl, aryl, heteroaryl, aryl(C 1 -C 6 )alkyl, heteroaryl(C 1 -C 6 )alkyl, and (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl, optionally substituted by one or more halogen atoms or (C 1 -C 4 )alkoxy; 
         R 3  is H or is selected from the group consisting of —OH, hydroxy(C 1 -C 6 )alkyl, —N(R 5 R 6 ), and —N(R 5 )CO(R 6 ); 
         R 5  and R 6  are independently H or (C 1 -C 6 )alkyl; 
       
       or a pharmaceutically acceptable salt thereof. 
     
     
       2. A compound or salt according to  claim 1 , wherein R 1  is H or is selected from the group consisting of (C 3 -C 8 )cycloalkyl, aryl, heteroaryl, and aryl(C 1 -C 6 )alkyl; R 2  is selected from the group consisting of (C 3 -C 8 )cycloalkyl, aryl, heteroaryl, aryl(C 1 -C 6 )alkyl, heteroaryl(C 1 -C 6 )alkyl, and (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl; R 3  is H or is selected from the group consisting of —OH, hydroxy(C 1 -C 6 )alkyl, —N(R 5 R 6 ), and —N(R 5 )CO(R 6 ); X is —O— or —S—; and R is —H or (C 1 -C 4 )alkyl. 
     
     
       3. A compound or salt according to  claim 2 , wherein R 1  is H or is selected from the group consisting of cyclobutyl, cyclopentyl, phenyl, benzyl, cycloheptyl, thienyl, and cyclohexyl; R 2  is selected from the group consisting of phenyl, thienyl, cyclohexyl, triphenylmethyl, chlorophenyl, methoxyphenyl, and fluorophenyl; R 3  is H or is selected from the group consisting of —OH, —NH 2 , —CH 2 OH, —NHCOCH 3 ; X is —O—; and R is H or —CH 3 . 
     
     
       4. A compound or salt according to  claim 1 , wherein Y is —(CH 2 ) n — wherein n is an integer of 1 to 12 or is a group of formula Y1: 
       
         
           
           
               
               
           
         
         wherein: 
         A1 and A2 are, each independently, absent or are selected from the group consisting of (C 1 -C 6 )alkylene, (C 3 -C 8 )cycloalkylene, and (C 3 -C 8 )heterocycloalkylene; B is absent or is selected from the group consisting of (C 3 -C 8 )cycloalkylene, (C 3 -C 8 )heterocycloalkylene, arylene, and heteroarylene or is a group of formula B1: 
       
       
         
           
           
               
               
           
         
         C is absent or is selected from the group consisting of —O—, —OCO—, —C(O)O—, —S—, —N(R 4 )— or is one of the following C1-C10 groups: 
       
       
         
           
           
               
               
           
         
         wherein R 4  is H or is selected from the group consisting of (C 1 -C 8 )alkyl, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )heterocycloalkyl, aryl, and heteroaryl; D is selected from the group consisting of (C 1 -C 12 )alkylene, (C 2 -C 12 )alkenylene, and (C 2 -C 6 )alkynylene; Z is —H or —OH and Q is a group of formula Q1, Q2, Q3, Q4, Q5 or Q6: 
       
       
         
           
           
               
               
           
         
       
     
     
       5. A compound or salt according to  claim 4 , wherein Y is —(CH 2 ) n —, Z is OH and Q is a group of formula Q1: 
       
         
           
           
               
               
           
         
       
       according to formula (IA): 
       
         
           
           
               
               
           
         
       
     
     
       6. A compound or salt according to  claim 5 , wherein n is 4, 5, 6, 7 or 8. 
     
     
       7. A compound or salt according to  claim 1 , wherein Y is a divalent group of formula Y1: 
       
         
           
           
               
               
           
         
         wherein A1 is (C 3 -C 8 )cycloalkylene, B and C are absent, D is (C 1 -C 12 )alkylene, Z is OH and Q is a group of formula Q1: 
       
       
         
           
           
               
               
           
         
       
       according to formula (IB), wherein (C 3 -C 8 )cycloalkylene is represented by “cy” 
       
         
           
           
               
               
           
         
       
     
     
       8. A compound or salt according to  claim 4 , wherein A1 is piperinyl and D is hexylene. 
     
     
       9. A compound or salt according to  claim 1 , wherein Y is —(CH 2 ) n —, Z is H and Q is a group of formula Q3: 
       
         
           
           
               
               
           
         
       
       according to formula (IC): 
       
         
           
           
               
               
           
         
       
     
     
       10. A compound or salt according to  claim 9 , wherein n is 8. 
     
     
       11. A pharmaceutical composition, comprising a compound or salt according to  claim 1  and one or more pharmaceutically acceptable carriers and/or excipients. 
     
     
       12. A method for the treatment of a disease selected from the group consisting of asthma, chronic bronchitis, and chronic obstructive pulmonary disease, comprising administering an effective amount of a compound or salt according to  claim 1  to a subject in need thereof. 
     
     
       13. A combination of a compound or salt according to  claim 1  and one or more active ingredients selected from the group consisting of a corticosteroid, a P38 MAP kinase inhibitor, a IKK2 inhibitor, a HNE inhibitor, a PDE4 inhibitor, a leukotriene modulator, a NSAID, and a mucus regulator. 
     
     
       14. A pharmaceutical composition according to  claim 11 , which is in a form suitable to be administered by inhalation. 
     
     
       15. A pharmaceutical composition according to  claim 14  which is an inhalable powder, a propellant-containing metering aerosol, or a propellant-free inhalable formulation. 
     
     
       16. A device comprising a pharmaceutical composition according to  claim 14 , which is a single- or multi-dose dry powder inhaler, a metered dose inhaler, or a soft mist nebulizer. 
     
     
       17. A method according to  claim 12 , wherein said disease is asthma. 
     
     
       18. A method according to  claim 12 , wherein said disease is chronic bronchitis. 
     
     
       19. A method according to  claim 12 , wherein said disease is chronic obstructive pulmonary disease.